This application is a 371 of PCT/FR98/02038 filed Sep. 20, 1998.
The present invention relates to novel tricyclic compounds, their preparation process and the intermediates of this process, their use as medicaments and the pharmaceutical compositions containing them.
A subject of the present invention is the compounds of general formula (I): 
in which R1 represents a xe2x80x94CONHxe2x80x94[A]xe2x80x94[B]xe2x80x94COR6 group, xe2x80x94[A]xe2x80x94 representing a divalent radical derived from an acyclic, linear or branched saturated or unsaturated hydrocarbon, comprising 1 to 12 carbon atoms, substituted by the (Z) group or non substituted,
[B] representing a phenyl radical, a CH(Z) radical, or a single bond,
(Z) represents a hydrogen atom, a (D)0-6xe2x80x94NRaRb, (D)0-6xe2x80x94NHxe2x80x94SO2xe2x80x94Rc, (D)0-6xe2x80x94NHxe2x80x94CO2xe2x80x94Rc, (D)0-6xe2x80x94NHxe2x80x94COxe2x80x94Rc, (D)0-6xe2x80x94NHxe2x80x94SO2xe2x80x94NHxe2x80x94Rc, (D)0-6xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94Rc, (D)0-6xe2x80x94CO2xe2x80x94RC, (D)0-6xe2x80x94SO2xe2x80x94Rc, (D)0-6xe2x80x94CO-Rc or (D)0-6xe2x80x94Rc group in which (D)0-6 is a divalent radical derived from an acyclic, linear or branched, saturated or unsaturated hydrocarbon, comprising 0 to 6 carbon atoms,
Ra, Rb and Rc represent a hydrogen atom, a (CH2)0-3xe2x80x94Ar radical in which Ar represents a carbocyclic aryl group containing 6 to 18 carbon atoms, a (CH2)0-3xe2x80x94Het radical in which Het represents a radical derived from an aromatic or non aromatic, saturated or non saturated heterocycle, comprising 1 to 9 carbon atoms and 1 to 5 heteroatoms chosen from oxygen, nitrogen or sulphur atoms, a (CH2)0-3xe2x80x94Alk radical in which Alk represents a radical derived from a non aromatic, linear, branched or cyclic, saturated or unsaturated hydrocarbon, and comprising 1 to 12 carbon atoms, the Het, Ar and Alk radicals being able to be non substituted or substituted,
or, Ra and Rb represent together with the nitrogen atom to which they are linked a nitrogenous, aromatic or non aromatic, saturated or unsaturated heterocycle, optionally containing one or more heteroatoms chosen from oxygen, nitrogen or sulphur atoms, this radical being able to be substituted or non substituted,
R6 represents a hydroxyl radical, an Oxe2x80x94Alk, Oxe2x80x94Ar, NH2, NHxe2x80x94Alk, N(Alk)2 radical or the remainder of an L or D amino acid, Alk and Ar being as defined previously and being able to be substituted or non substituted,
R2 and R3 identical or different represent either a hydrogen atom, a hydroxyl radical, an Oxe2x80x94Alk radical or an Oxe2x80x94(CH2)0-3xe2x80x94Ar radical, Alk and Ar being as defined previously, or R2 and R3 form together a ring of the xe2x80x94Oxe2x80x94(CRdRe)nxe2x80x94Oxe2x80x94 type, n being an integer from 1 to 5, Rd and Re independently of one another represent a hydrogen atom, an alkyl radical containing 1 to 6 carbon atoms, or a phenyl radical,
R4 represents a hydrogen atom, a halogen atom, a hydroxyl, amino, nitro, cyano, CF3, acyl or acyloxy group containing 1 to 12 carbon atoms alkyl, alkenyl, alkynyl, alkylthio, alkoxy, alkylamino, dialkylamino, dialkylaminoalkyl, dialkylaminoalkyloxy group, in which the alkyl term contains 1 to 6 carbon atoms,
R5 represents a hydrogen atom, a hydroxyl radical, a halogen atom, an Oxe2x80x94Alk radical or an Oxe2x80x94(CH2)0-3xe2x80x94Ar radical, Alk and Ar being as defined previously,
G represents,
either a radical of formula G1
in which Rh is a hydrogen atom or an (Alk) group as defined previously and (Hetxe2x80x2) is a heterocycle of general formula: 
in which (H) forms, with the Nxe2x95x90Cxe2x80x94NHxe2x80x94 unit, the remainder of an aromatic or non aromatic, mono or bicyclic, saturated or non saturated heterocycle comprising 1 to 9 carbon atoms and 2 to 5 heteroatoms chosen from oxygen, nitrogen and sulphur atoms, this radical being able to be substituted or non substituted,
or an NRaRb radical (radical G2), Ra and Rb being as defined above,
or a (Het) radical (radical G3) as defined above,
or an xe2x80x94NRhxe2x80x94C(xe2x95x90X)xe2x80x94NHRc radical (radical G4), in which X is a sulphur, oxygen or NH atom, Rh and Rc are as defined previously,
or an xe2x80x94NRhxe2x80x94SO2Rc radical, (radical G5), in which Rh and Rc are as defined previously, the dotted lines represent an optional second bond, as well as the addition salts with acids, bases and esters, R1, R2 and R3 can be in position 8, 9 or 10 of the tricycle.
By compound of formula (I) is meant all the possible geometric isomers and stereoisomers taken individually or in a mixture.
When xe2x80x94[A]xe2x80x94 represents a divalent radical derived from an acyclic, linear or branched, saturated or unsaturated, hydrocarbon comprising 1 to 12 carbon atoms, the alkylene radicals of formula xe2x80x94(CH2)nxe2x80x94, in which n represents an integer comprised between 1 and 12, such as xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94CH2CH2CH2xe2x80x94 or xe2x80x94CH2CH2CH2CH2xe2x80x94, or the alkenylene or alkynylene radicals such as xe2x80x94CHxe2x95x90CHxe2x80x94CH2xe2x80x94 or xe2x80x94Cxe2x95x90xe2x80x94Cxe2x80x94CH2xe2x80x94 are designated in particular.
When these divalent radicals are branched, it can be radicals such as xe2x80x94CH(CH3)xe2x80x94, xe2x80x94C(Me)2, xe2x80x94CH2xe2x80x94C(Me)2xe2x80x94, xe2x80x94CH(Et)xe2x80x94, xe2x80x94CH(Cxe2x89xa1xe2x89xa1CH)xe2x80x94 or xe2x80x94C(Cxe2x89xa1CH)(Et)xe2x80x94.
When [B] represents a divalent radical xe2x80x94Phxe2x80x94, the COR6 group can be in ortho, meta or para position. It is preferably found in para position.
When (D)0-6 is a divalent radical derived from an acyclic, linear or branched, saturated or unsaturated, hydrocarbon comprising 0 to 6 carbon atoms, (D)0-6 is chosen from the values of [A] mentioned above. By (D)0 is meant the absence of this radical which reverts to having a single covalent bond. (D) will preferably be a single bond or a (CH2)n group, n being an integer chosen from 1, 2 or 3 .
When Ra, Rb and Rc represent a (CH2)0-3xe2x80x94Ar, (CH2)0-3xe2x80x94Het, (CH2)0-3xe2x80x94Alk group, (CH2)0-3 represents either a single bond in the case of (CH2)0, or xe2x80x94CH2xe2x80x94, xe2x80x94(CH2)2xe2x80x94 or xe2x80x94(CH2)3xe2x80x94 radicals.
By the term (Ar) representing a carbocyclic aryl group containing 6 to 18 carbon atoms, is meant a radical derived from an aromatic cyclic hydrocarbon such as the phenyl, naphthyl, phenanthrenyl radical or a radical derived from a condensed bicyclic or tricyclic hydrocarbon comprising a benzene ring such as indanyl, indenyl, dihydronaphtyl, tetrahydronaphtyl or fluorenyl. The junction is carried out at the level of the benzene ring. It is preferably phenyl.
By the term (Het) representing a radical derived from an aromatic or non aromatic, saturated or non saturated heterocycle, comprising 1 to 9 carbon atoms and 1 to 5 heteroatoms chosen from oxygen, nitrogen and sulphur atoms, is designated in particular:
heterocyclic monocyclic radicals, for example thienyl, furyl, pyrannyl, pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, thiazolyl, oxazolyl, furazannyl, pyrrolinyl, imidazolinyl, pyrazolinyl, thiazolinyl, triazolyl, tetrazolyl radicals,
heterocyclic condensed rings, for example benzofurannyl, benzothienyl, benzimidazolyl, benzothiazolyl, naphtho[2,3-b]thienyl, thianthrenyl, isobenzofurannyl, chromenyl, xanthenyl, phenoxathiinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl, purinyl, quinolizinyl, isoquinolyl, quinolyl, phthalazinyl, naphthyridinyl, quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, carbazolyl, beta-carbolinyl, acridinyl, phenazinyl, phenothiazinyl, phenoxazinyl, indolinyl, isoindolinyl, imidazopyridyl, imidazopyrimidinyl or also polycyclic condensed systems constituted by heterocyclic monocyclics as defined above such as for example furo[2,3-b]pyrrole or thieno[2,3-b]furan,
or saturated heterocycles such as pyrrolidine, piperidine, morpholine.
This term (Het) includes moreover the values of (Hetxe2x80x2) as defined previously.
By the term (Alk) representing a radical derived from a non aromatic, linear, branched or cyclic, saturated or unsaturated hydrocarbon, is designated in the case of acyclic hydrocarbons alkyl radicals such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, n-pentyl, n-hexyl, 2-methyl pentyl, 2,3-dimethyl butyl, n-heptyl, 2-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethyl pentyl, 3-ethylpentyl, n-octyl, 2,2-dimethylhexyl, 3,3-dimethylhexyl, 3-methyl-3-ethylpentyl, nonyl, 2,4-dimethylheptyl or n-decyl, alkenyl radicals such as vinyl, propenyl, isopropenyl, allyl, 2-methylallyl, butenyl or isobutenyl, or alkynyl radicals such as ethynyl, propynyl, propargyl, butynyl or isobutynyl, and in the case of cyclic radicals, cycloalkyl radicals, such as cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or adamantyl.
When Ra and Rb represent together with the nitrogen atom to which they are linked a nitrogenous heterocycle, it is in particular the following saturated heterocycles morpholine, piperidine, piperazine, pyrrolidine, or unsaturated heterocycles such as pyrimidine, pyridine or pyrazine.
When R2, R3, R4 and R5 represent an Oxe2x80x94(Alk) radical containing 1 to 12 carbon atoms, it is preferably methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy, allenyloxy or propargyloxy radicals. When R2, R3, R4 and R5 represent an Oxe2x80x94(CH2)0-3xe2x80x94Ar radical phenylethoxy and phenylpropyloxy radicals are preferably meant.
When R2 and R3 form together a ring of xe2x80x94Oxe2x80x94(CRdRe)nxe2x80x94Oxe2x80x94 type, n being an integer from 1 to 5, it is in particular the xe2x80x94Oxe2x80x94CH2xe2x80x94O, Oxe2x80x94C(Me)2xe2x80x94O, Oxe2x80x94C(Ph)2xe2x80x94O, Oxe2x80x94C(CH3) (Ph)xe2x80x94O radicals, R2 and R3 are imperatively in ortho position relative to each other.
When R6 represents an Oxe2x80x94Alk or Oxe2x80x94Ar radical, Alk and Ar being substituted or non substituted, it is in particular the following radicals: (C1-C8) alkoxy, (C1-C14)-aryl (C1-C8)-alkoxy, (C6-C14) aryloxy, (C1-C8) alkylcarboxyloxy, (C1-C8) dialkylaminocarbonylmethoxy, (C6-C14) aryl (C1-C8) dialkylaminocarbonylmethoxy.
When R6 represents an NHxe2x80x94alk, NH(alk)2 or NHxe2x80x94Ar radical, it is in particular the (C1-C8) alkylamino, di-(C1-C8) alkylamino, (C6-C14) aryl (C2-C8) alkylamino, (C6-C14) arylamino radicals.
When R6 represents the remainder of an amino acid it can be L or D amino acid.
The L or D amino acids can be natural or not natural. Preferably it is xcex1-amino acids. For example, those described in Houben-Weyl, Methoden der organischen Chemie, Band XV/1 and 2, Georg Thieme Verlag, Stuttgart, 1974: Aad, Abu, xcex3Abu, Abz, 2ABz, xcex5Aca, Ach, Acp, Adpd, Ahb, Aib, xcex2Aib, Ala, xcex2Ala, xcex94ala, Alg, All, Ama, Amt, Ape, Apm, Apr, Arg, Asn, Asp, Asu, Aze, Azi, Bai, Bph, Can, Cit, Cys, (Cys)2, Cyta, Daad, Dab, Dadd, Dap, Dapm, Dasu, Djen, Dpa, Dtc, Fel, Gln, Glu, Gly, Guv, hAla, hArg, hCys, hGln, hGlu, His, hlle, hLeu, hLys, hMet, hphe, hpro, hSer, hThr, hTrp, hTyr, Hyl, Hyp, 3Hyp, Ile, Ise, Iva, Kyn, Lant, Lcn, Leu, Lsg, Lys, xcex2Lys, xcex94lys, Met, Mim, Min, nArg, Nle, Nva, Oly, Orn, Pan, Pec, Pen, Phe, Phg, Pic, Pro, xcex94pro, Pse, Pya, Pyr, Pza, Qin, Ros, Sar, Sec, Sem, Ser, Thi, xcex2Thi, Thr, Thy, Thx, Tia, Tle, Tly, Trp, Trta, Tyr, Val, tert-butylglycine (Tbg), Neopentylglycine (Npg), Cyclohexylglycine (Chg), Cyclohexylalanine (Cha), 2-Thienylalanine (Thia), 2,2-diphenylaminoacetic acid, 2-(p-tolyl)2-phenylamino acetic acid, 2-(p-chlorophenyl) amino acetic acid, or also 2-pyrrolidine acetic acid, 1,2,3,4-tetrahydroisoquinoline 3-acetic acid, decahydroisoquinoline 3-acetic acid, octahydroisoindol 2-acetic acid, decahydroquinoline 2-acetic acid, octahydrocyclopenta[b]pyrrol 2-carboxylic acid, 2-azabicyclo[2,2,2]octan-3-carboxylic acid, 2-azabicyclo [2,2,1]heptan-3-carboxylic acid, 2-azabicyclo[3,1,0]hexan-3-carboxylic acid, 2-azaspiro[4,4]nonan-3-carboxylic acid, 2-azaspiro[4,5]decan-3-carboxylic acid, spiro (bicyclo [2,2,1]heptan)-2,3-pyrrolidin-5-carboxylic acid, spiro (bicyclo[2,2,2]octan-2,3-pyrrolidin-5-carboxylic acid, 2-azatricyclo[4,3,0,16,9]decan-3-carboxylic acid, decahydrocyclohepta[b]pyrrol-2-carboxylic acid, decahydrocycloocta[c]pyrrol-2-carboxylic acid, octahydrocyclopenta[c]pyrrol-2-carboxylic acid, octahydroisoindol-1-carboxylic acid, 2,3,3a,4,6a-hexahydrocyclopenta [b]pyrrol-2-carboxylic acid, 2,3,3a,4,5,7a-hexahydroindol-2-carboxylic acid, tetrahydrothiazol-4-carboxylic acid, isoxazolidin-3-carboxylic acid, pyrazolidin-3-carboxylic acid, hydroxypyrrolidin-2-carboxylic acid, which if appropriate, can be substituted (see the following formulae): 
The heterocycle remainders described above are known, for example, in the following Patents or Patent Applications: U.S. Pat. No. 4,344,949; U.S. Pat. No. 4,374,847; U.S. Pat. No. 4,350,704; EP-A-29.488; EP-A-31.741; EP-A-46.953; EP-A-49.605; EP-A-49.658; EP-A-50.800; EP-A-51.020; EP-A-52.870; EP-A-79.022; EP-A-84.164; EP-A-89.637; EP-A-90.341; EP-A-90.362; EP-A-105.102; EP-A-109.020; EP-A-111.873; EP-A-271.865 and EP-A-344.682.
Moreover the amino acids can be in the form of an ester or an amide, such as for example, methyl ester, ethyl ester, isopropyl ester, isobutyl ester, tert-butyl ester, benzyl ester, ethylamide, semicarbazide or xcfx89-amino (C2-C8)-alkylamide.
Finally, the functional groups of these amino acids can be protected. The appropriate protective groups such as the protective groups of urethanes, the protective groups of carboxyl or the protective groups of the side chains are described by Hubbuch, Kontakte (Merck)1979, No. 3, p. 14-23 and by Bxc3xcllesbach, Kontakte (Merck)1980, No. 1, p. 23-35.
For example Aloc, Pyoc, Fmoc, Tcboc, Z, Boc, Ddz, Bpoc, Adoc, Msc, Moc, Z(NO2), Z(Haln), Bobz, Iboc, Adpoc, Mboc, Acm, tertbutyl, Obzl, Onbzl, Ombzl, Bzl, Mob, Pic, Trt can be mentioned.
When G is a radical of formula G1
and (Hetxe2x80x2) is a heterocycle of general formula: 
in which (H) forms, with the Nxe2x95x90Cxe2x80x94NHxe2x80x94 unit, an aromatic or non aromatic, mono or bicyclic, saturated or non saturated heterocycle, comprising 1 to 9 carbon atoms and 2 to 5 heteroatoms chosen from oxygen, nitrogen and sulphur atoms, this radical being able to be substituted or non substituted, G1 represents in particular the following heterocycles: 
in which p represents an integer from 1 to 4 .
When G is an xe2x80x94NRaRb radical (called G2), Ra and Rb can be a hydrogen atom, a (CH2)0-3xe2x80x94Ar, (CH2)0-3xe2x80x94Het or (CH2)0-3xe2x80x94Alk radical. The Ar, Het and Alk groups can also be substituted by the groups as defined below. G2 can be in particular an NH2, NHxe2x80x94Alk such as NHMe, NHEt, N(Alk)2 such as NMe2, NEt2, NMeEt, NHxe2x80x94(CH2)0-1xe2x80x94Ar such as NHPh, NHCH2Ph or NHCH2Het such as NHCH2-pyrrol-2-yl group.
When Ra is a hydrogen atom or an (Alk) group and when Rb is a (Hetxe2x80x2) group, the values of G1 are found.
When Ra and Rb form together with the nitrogen atom to which they are linked a nitrogenous heterocycle, it is in particular the heterocyclic groups described above, these being able to be substituted or non substituted.
When G is a (Het) radical (radical G3) this radical being able to be substituted or non substituted, it is in particular the heterocycles listed above and in particular the heterocycles of general formula (Hetxe2x80x2) as defined above. When this heterocycle is linked at the level of its nitrogen atom, the values of G2 are found in which Ra and Rb form a heterocycle with the nitrogen atom which carries them.
When G is an xe2x80x94NRhxe2x80x94C(xe2x95x90X)xe2x80x94NHRc radical (radical G4), or NRhSO2Rc radical (radical G5), in which X is a sulphur, oxygen or NH atom, Rh and Rc are as defined previously. It is in particular the xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2, xe2x80x94NHxe2x80x94C(xe2x95x90O)xe2x80x94NH2 or xe2x80x94NHxe2x80x94C(xe2x95x90S)xe2x80x94NH2, xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHCH2xe2x80x94Ar such as xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHCH2Ph, xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHCH2xe2x80x94Het, xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHCH2xe2x80x94Hetxe2x80x2, xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH-Alk such as xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94NHCH3, or xe2x80x94NHxe2x80x94SO2Ph groups, the Ar, Het, Hetxe2x80x2 or Alk groups being substituted or non substituted.
The optional substituents of the (Alk), (Ar), (Het), (Hetxe2x80x2) or NRaRb radicals forming a heterocycle, are preferably the following radicals:
halogen: fluorine, chlorine, bromine, iodine,
alkyl, alkenyl, alkynyl containing 1 to 12 carbon atoms such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, vinyl or allenyl. These radicals being themselves optionally substituted by one or more halogen atoms, for example fluorine such as trifluoromethyl.
oxo, cyano, nitro, formyl, carboxy and carboxyalkyl containing 1 to 6 carbon atoms, carboxamide,
alkoxy containing 1 to 12 carbon atoms such as methoxy, ethoxy, propyloxy, isopropyloxy, butyloxy,
alkylthio containing 1 to 12 carbon atoms such as methylthio, ethylthio, propylthio, isopropylthio, butylthio,
amino, alkylamino containing 1 to 12 carbon atoms such as methylamino or ethylamino, dialkylamino containing 2 to 24 carbon atoms such as dimethylamino, diethylamino, methylethylamino, each of these dialkylamino radicals being optionally in oxidized form,
aminoalkyl containing 1 to 12 carbon atoms such as aminomethyl or aminoethyl,
dialkylaminoalkyl containing 3 to 25 carbon atoms such as dimethylamino methyl or ethyl,
dialkylaminoalkyloxy containing 3 to 25 carbon atoms such as dimethylaminoethyloxy,
optionally acylated hydroxyl containing 1 to 12 carbon atoms, for example acetoxy,
acyl containing 1 to 12 carbon atoms such as formyl, acetyl, propionyl, butyryl, isobutyryl, valeryl, isovaleryl, succinyl, pivaloyl benzoyl optionally substituted for example by a chlorine, iodine or fluorine atom. The chloroacetyl, dichloroacetyl, trichloroacetyl, bromoacetyl or trifluoroacetyl radicals can be mentioned,
carbocyclic or heterocyclic aryl such as phenyl, furyl, thienyl, pyridinyl or aralkyl such as benzyl, these radicals themselves being optionally substituted by the halogen, alkyl, alkoxy, alkylthio, amino alkyl or dialkylamino radicals indicated above.
When Ar represents a phenyl, this can be substituted by an Oxe2x80x94(CRdRe)nxe2x80x94O group as defined previously.
Of course, one or more substituents, identical or different, can be present. In the case of (Het) the substituents can be at the level of the NH group or the carbon atom.
These substituents also illustrate the definition of R4.
It is of course understood that when R1, R2, R3, R4, R5, R6, Ra, Rb, Rc represent an alkyl, aryl or heterocycle group as defined above, they can be identical or different independently of each other.
The invention naturally extends to the salts of the compounds of formula (I), such as for example the salts formed when the compounds of formula (I) comprise an amino or amino guanidine function, with the following acids: hydrochloric, hydrobromic, nitric, sulphuric, phosphoric, acetic, trifluoroacetic, formic, propionic, benzoic, maleic, fumaric, succinic, tartaric, citric, oxalic, glyoxylic, aspartic, alkanesulphonic acids such as methane or ethanesulphonic acids, arenesulphonic acids, such as benzene or paratoluene sulphonic acids and arylcarboxylic acid, or when the compounds of formula (I) comprise an acid function, with the salts of alkali or alkaline-earth metals or of ammonium optionally substituted.
The invention also extends to the esters of the compounds of formula (I).
In a first preferred group, a subject of the invention is the compounds of general formula (I) as defined previously, corresponding to general formula (Ixe2x80x2): 
in which Rxe2x80x21 represents a
xe2x80x94CONHxe2x80x94[Axe2x80x2]xe2x80x94[Bxe2x80x2]xe2x80x94CORxe2x80x26 group, xe2x80x94[Axe2x80x2]xe2x80x94 representing a divalent alkylene, alkenylene or alkynylene radical containing 1 to 6 carbon atoms substituted by the group (Zxe2x80x2) or non substituted, [Bxe2x80x2] representing a CH(Zxe2x80x2) radical or a single bond,
(Zxe2x80x2) represents a hydrogen atom, a
(CH2)0-6xe2x80x94NRaRb, (CH2)0-6xe2x80x94NHxe2x80x94SO2xe2x80x94Rc, (CH2)0-6xe2x80x94NHxe2x80x94CO2xe2x80x94Rc, (CH2)0-6xe2x80x94NHxe2x80x94COxe2x80x94Rc, (CH2)0-6xe2x80x94NHxe2x80x94SO2xe2x80x94NHxe2x80x94Rc, (CH2)0-6xe2x80x94NHxe2x80x94COxe2x80x94NHxe2x80x94Rc, (CH2)0-6xe2x80x94CO2xe2x80x94Rc, (CH2)0-6xe2x80x94SO2xe2x80x94Rc, (CH2)0-6xe2x80x94COxe2x80x94Rc or (CH2)0-6xe2x80x94Rc group, Ra, Rb and Rc being as defined previously, Rxe2x80x26 represents an OH, amino or alkoxy radical containing 1 to 8 carbon atoms, optionally substituted by one or more radicals chosen from the hydroxy, amino, phenylalkylamino or dialkylamino radicals, Rxe2x80x22 and Rxe2x80x23 represent a hydrogen atom or a methoxy radical, and G is as defined previously, the dotted lines represent an optional second bond, as well as the addition salts with acids, bases and esters.
In a second preferred group, a subject of the invention is the compounds of general formula (I) as defined previously in which R6 represents an xe2x80x94OH, xe2x80x94OCH3, xe2x80x94OCH2CH3, xe2x80x94Oxe2x80x94(CH2)2xe2x80x94OH, xe2x80x94Oxe2x80x94CH2xe2x80x94CH (OH)xe2x80x94CH2OH, xe2x80x94Oxe2x80x94(CH2)2xe2x80x94NH2, xe2x80x94Oxe2x80x94(CH2)2xe2x80x94N(CH3)2, xe2x80x94NH2 or xe2x80x94Oxe2x80x94(CH2)-phenyl group, as well as the addition salts with acids, bases and esters.
In a third preferred group, a subject of the invention is the compounds of general formula (I) as defined previously in which R1 represents a xe2x80x94CONHxe2x80x94CH(Zxe2x80x2)xe2x80x94CH2CO2H or xe2x80x94CONHxe2x80x94CH2xe2x80x94CH(Zxe2x80x2)xe2x80x94CO2H group, as well as the addition salts with acids, bases and esters.
In a fourth preferred group, a subject of the invention is the compounds of general formula (I) as defined previously, in which (Zxe2x80x2) is a substituted or non substituted aryl or heteroaryl group, as well as the addition salts with acids, bases and esters.
In a fifth preferred group, a subject of the invention is the compounds of general formula (I) as defined previously, in which (Zxe2x80x2) is the (CH2)0-6xe2x80x94NHxe2x80x94CO2xe2x80x94Rc or (CH2)0-6xe2x80x94NHRb group, Rb and Rc being as defined previously, as well as the addition salts with acids, bases and esters.
In a sixth preferred group, a subject of the invention is the compounds of general formula (I) as defined previously, in which Rb and Rc represent the (CH2)0-3xe2x80x94Ar or (CH2)0-3xe2x80x94Alk groups, Ar and Alk being as defined previously and being able to be substituted or non substituted, as well as the addition salts with acids, bases and esters.
In a seventh preferred group, a subject of the invention is the compounds of general formula (I) as defined previously, in which G is a group G4 of formula xe2x80x94NHxe2x80x94C(xe2x95x90NH)xe2x80x94 NHRc, Rc being as defined previously, as well as the addition salts with acids, bases and esters.
In an eighth preferred group, a subject of the invention is the compounds of general formula (I) as defined previously, in which G is a group G4 of formula NHxe2x80x94C(xe2x95x90NH)xe2x80x94NH2, as well as the addition salts with acids, bases and esters.
In a ninth preferred group, a subject of the invention is the compounds of general formula (I) as defined previously, in which G is an xe2x80x94NHxe2x80x94(Hetxe2x80x2) group as defined previously and in particular, 
being an integer equal to 2, 3 or 4, these heterocycles being substituted or non substituted, as well as the addition salts with acids, bases and esters.
In a tenth preferred group, a subject of the invention is the compounds of general formula (I) as defined previously, in which G is the 
group, p being an integer equal to 2, 3 or 4, as well as the addition salts with acids, bases and esters.
In an eleventh preferred group, a subject of the invention is the compounds of formula (I) as defined previously, the names of which follow:
3-[[[4-[(4,5-dihydro-1H-imidazol-2-yl)hydrazono]-9,10-dimethoxy-1,2,3,4,5,6-hexahydro-8-benz[e]azulenyl]-carbonyl]amino]-N-[(phenylmethoxy)carbonyl]-DL-alanine
3-[[[9,10-dimethoxy-1,2,3,4,5,6-hexahydro-4-[(1,4,5,6-tetrahydropyrimidin-2-yl)]-hydrazono]-8-benz[e]azulenyl]carbonyl]amino]-N-[(phenylmethoxy)carbonyl]-DL-alanine
beta-[[[4-[(4,5-dihydro-1H-imidazol-2-yl) hydrazono]-1,2,3,4,5,6-hexahydro-8-benz[e]azulenyl]carbonyl]-amino]-3-pyridine-3-yl-propanoic acid
beta-[[[4([(4,5-dihydro-1H-imidazol-2-yl) hydrazono]-(1,2,3,4,5,6-hexahydro-4-oxo-8-benz[e] azulenyl]carbonyl]-amino]-3-(1,3-benzodioxole-5-yl-propanoic acid.
A subject of the invention is also a process for the preparation of the compounds of general formula (I) comprising the following stages:
a) action of an activating agent of the alcohol function then a carbonylation reaction of the compounds of formula (II): 
in which R2, R3, R4 and R5 are as described previously with the exception of the hydroxyl value,
in order to obtain the ester of formula (IIIa): 
Rf being an alkyl radical containing 1 to 4 carbon atoms,
b) saponification of the ester of formula (IIIa) in order to obtain the corresponding acid of formula (IIIb): 
c) amidification reaction of the acid of formula (IIIb) by the action of a compound of formula (F1), if appropriate in the form of salt:
H2Nxe2x80x94[A]xe2x80x94[B]xe2x80x94COR6xe2x80x83xe2x80x83(F1)
[A], [B] and R6 being as defined previously, [A] or [B] can also represent the xe2x80x94CHxe2x80x94NHP group, P being a protective group of the amine function, in order to obtain a compound of formula (IIIc): 
d) action on the compound of formula (IIIc) of a compound of formula (F2):
Gxe2x80x94NH2xe2x80x83xe2x80x83(F2)
G being as defined previously, in order to obtain a compound of formula (I),
e) a compound of formula (I) which if appropriate is subjected in an appropriate order:
to the action of a base or an acid in order to detach the ester and to obtain the corresponding acid,
to the action of a dealkylation agent,
to the action of a deprotection agent of the NHxe2x80x94P function in beta of COxe2x80x94R6 when [A] or [B] represents the CHxe2x80x94NHP group,
to the formation of the NHxe2x80x94SO2Rc, NHxe2x80x94CO2Rc, NHCORc, NHxe2x80x94SO2xe2x80x94NHxe2x80x94Rc, NHxe2x80x94COxe2x80x94NHRc group the from the corresponding amine,
to the action of an acid or a base in order to obtain the corresponding salts or to the action of an esterification agent in order to obtain the corresponding esters.
The carbonylation reaction is carried out in particular according to the method described by P. Prince, D. Richard and D. Gandour in Synlett (1991)405, and in xe2x80x9cPalladium Reagents in Organic Synthesisxe2x80x9d ed. Hech R. F. Academic Press N.Y. Chap. 8 (1995).
The activation of the alcohol can be carried out in particular using the triflic anhydride of formula (CF3SO2)2O in the presence of a base such as pyridine in order to form the corresponding triflate of formula (OSO2CF3).
The action of the compound of formula H2Nxe2x80x94[A]xe2x80x94[B]xe2x80x94COR6 (F2) preferably is carried out in basic medium, in a solvent such as dimethylformamide.
The action of NH2xe2x80x94G (F2) is carried out, either without solvent, or in an alcoholic solvent such as ethanol, isopropanol or butanol. The synthon NH2xe2x80x94G is optionally used in the form of a salt such as the hydrochloride or the hydrobromide.
The saponification reaction of the ester function is carried out for example by the action of an alkaline base such as soda or potash in tetrahydrofuran or a lower alcohol such as methanol or ethanol. The ester can also be detached in acid medium according to methods known to a person skilled in the art.
The dealkylation reaction allowing access to the products of formula (I) with R2, R3, R4 or R5 representing hydroxyls is carried out in the presence of aluminium chloride or boron tribromide.
The functionalization of NH2, [A] or [B] representing CH(NH2) or CH(NH2.Hcl), is carried out according to the standard methods known in organic chemistry.
The formation of NHSO2Rc from the corresponding amine is preferably carried out by the action of RcSO2Hal in the presence of a base for example triethylamine.
The formation of NHCO2Rc from the corresponding amine is preferably carried out by the action of RcOH according to the method described in J. Org. Chem., 61, 3929-3934 after having previously reacted the triphosgene in the presence of sodium bicarbonate in order to intermediately obtain the isocyanate.
The salification reactions can be carried out under the usual conditions. For example, to salify the terminal CO2H group of R1, the operation is carried out in the presence of a sodium salt such as sodium carbonate or sodium or potassium acid carbonate.
Similarly, salification of the amine or the amino-guanidine which can be represented by G, with an acid, is carried out under the usual conditions. For example the operation is carried out with hydrochloric acid, for example in an ethereal solution.
The optional esterification of the products is carried out under the standard conditions known to a person skilled in the art.
In general the operation is carried out by reacting the acid of formula (I) or a functional derivative with a reagent which is capable of introducing the ester group a non-exhaustive list of which is given above in the definition of R6.
The products of general formula (F1) or (F2) are known or prepared according to methods known to a person skilled in the art.
The order in which the different reagents are grafted can also be reversed, namely the compound of formula (II) is subjected to the action of compound of formula F2 in order to intermediately obtain the product of formula (IIId): 
which is then used in the reactions as described in Stages a), b), c) and if appropriate e), in order to obtain the compounds of formula (I).
In this case, if appropriate, it will be necessary to provide protection for group G of the product of formula (IIId), then after introduction of (F1) or (F2), a deprotection according to methods known to a person skilled in the art (T. W. GREENE Protective Groups in Organic Synthesis. John Wiley and Sons Inc. 1991).
The deprotection reaction of the NHxe2x80x94P group in beta position of COxe2x80x94R6, [A] or [B] representing the CHxe2x80x94NHP group, is also carried out according to methods known to a person skilled in the art, in particular when P represents the CO2tBu group, by a decarboxylation reaction such as for example by the action of hydrochloric acid.
Bone is constantly subjected to a dynamic process which includes bone resorption and bone formation. These processes are mediated via specialized cells. Bone formation is the result of the deposition of a mineral matrix by the osteoblasts and bone resorption is the result of the dissolution of this bone matrix by osteoclasts. Osteoporosis is characterized by a dry loss of this bone matrix. An activated mature osteoclast resorbs the bone after adhesion to the bone matrix via the secretion of proteolytic enzymes and protons inside the adhesion zone, resulting in depressions or hollows on the bone surface which appear at the time when the osteoclast detaches itself from the bone.
The compounds of formula (I) as well as their pharmaceutically acceptable addition salts have useful pharmacological properties. These compounds inhibit bone resorption which is mediated via the osteoclasts.
The compounds of the invention are thus useful in the treatment of diseases caused by the loss of bone matrix, in particular, osteoporosis, malignancy hypercalcemia, osteopenia due to bone metastasis, parodontitis, hyperparathyroidism, the periarticular erosions in rhumatoid arthritis, Paget""s disease, osteopenia induced by immobilization, treatments with glucocorticoids or male or female sex hormone deficiencies.
They can also be used for the treatment of inflammatory, cancerous and cardiovascular disorders including atherosclerosis, restenosis.
Finally, they can be used as inhibitors of angiogenesis and therefore in the treatment of tumors, by inhibition of their neovascularization, diabetic retinopathies and nephropathies.
Recent studies have shown that fixation of the osteoclast to the bone is mediated by receptors: the integrins.
Integrins are a superfamilly of receptors mediating the cell/cell adhesion processes and more particularly cell/matrix, including in particular xcex12bxcex23 as a blood platelet receptor (fibrinogen) and xcex1vxcex23 as vitronectin receptor, bone sialoproteins such as osteopontin and thrombospondin.
These receptors which are proteinic heterodimers composed of two sub-units xcex1 and xcex2, have divalent ion fixation sites such as Ca2+ in particular and a recognition site for their ligand predefined by the quality of their sub-units.
The xcex1vxcex23 receptor is a transmembrane glycoprotein which is expressed in a large number of cells including endothelial cells, smooth muscle cells, osteoclast and cancerous cells which thus leads to pluripotentiality of the compounds according to the invention.
The xcex1vxcex23 receptors expressed at the level of the osteoclast membrane are the basis of the adhesion/resorption process, contribute to the organisation of the cell cytoskeleton, and are involved in osteoporosis (Ross et al., J. Biol. Chem., 1987, 262, 7703).
The xcex1vxcex23 receptors expressed at the level of the smooth muscle cells of the aorta, stimulate their migration towards the neointima, which leads to the formation of atherosclerosis and the occurrence of post-angioplastic recurrence of stenosis (Brown et al, cardiovascular Res. (1994), 28, 1815).
The endothelial cells secrete growth factors which are mitogens for the endothelium and can contribute to the formation of new blood vessels (Angiogenesis). The angiogenic stimulation causes the formation of new blood vessels.
The antagonists of integrin xcex1vxcex23 can thus lead to a regression of cancerous tumors by inducing the apoptosis of the angiogenic blood vessels. (Brook et al. Cell (1994)79, 1157).
The natural ligands of integrin xcex1vxcex23 contain all the RGD unit (Arg-Gly-Asp). The peptides containing this RGD unit as well as the anti xcex1vxcex23 anti-bodies are known for their inhibitory capacity on the resorption of dentin, obstruction of the adhesion of the osteoclasts on the mineralized matrices (Horton et al. Exp. Cell. Res. (1991), 195, 368).
The peptide Echistatin isolated from snake venom also containing an RGD unit is described as an inhibitor of the adhesion of the osteoclasts to bone, and is therefore a powerful inhibitor of bone resorption in tissues cultured in vitro (Sato et al. J. Cell. Biol. (1990), 111, 1713) and in vivo in the rat (Fisher et al. Endocrinology (1993), 132, 1441).
The compounds of formula (I) as well as their pharmaceutically acceptable addition salts and their esters can have in particular an affinity vis-à-vis the receptor of vitronectin xcex1vxcex23 or vis-à-vis other integrins having vitronectin (xcex1vxcex21, xcex1vxcex25, xcex1vxcex23) for ligand by inhibiting the bond to their natural ligand.
This property thus renders the compounds of the invention of use for the prevention or the treatment of diseases the underlying pathology of which is caused by the ligands or cells which interact with the vitronectin receptor.
These compounds can also have an activity vis-à-vis other integrins which interact with their ligand via the tripeptide sequence RGD, giving them pharmacological properties which can be used for treating pathologies associated with these receptors.
This activity vis-à-vis integrins therefore renders the compounds of the invention of use in the treatment of numerous diseases such as those mentioned above or in the article by Dermot Cox DNandP 8(4) May 1995, 197-205 the content of which is included in the present Application.
Therefore a subject of the invention is the compounds of formula (I) as medicaments, as well as their pharmaceutically acceptable addition salts or their esters.
Among the medicaments according to the invention, the compounds described in the experimental part can be particularly mentioned.
Among these products, a more particular subject of the invention is, as medicaments, the compounds of formula (I) listed previously.
The dosage varies as a function of the illness to be treated and the administration route: it can vary for example from 1 mg to 1000 mg per day in an adult by oral route.
The invention extends to the pharmaceutical compositions containing at least one medicament as defined above as active ingredient.
The compounds of formula (I) are used by digestive, parenteral or local route, for example by percutaneous route. They can be prescribed in the form of plain or coated tablets, gelatin capsules, granules, suppositories, pessaries, injectable preparations, ointments, creams, gels, microspheres, nanospheres, implants, patches which are prepared according to the usual methods.
The active ingredient or ingredients can be incorporated with excipients usually employed in these pharmaceutical compositions, such as talc, gum arabic, lactose, starch, magnesium stearate, cocoa butter, aqueous or non-aqueous vehicles, fatty substances of animal or vegetable origin, paraffin derivatives, glycols, various wetting, dispersing or emulsifying agents, preservatives.
The products of formula (II), in which the hydroxy radical is in position 10, R2 in position 8 and R3 in position 9, represent an Oxe2x80x94(Alk) or Oxe2x80x94(CH2)0-3xe2x80x94Ar group, R4 and R5 are hydrogen atoms, are prepared according to the method described in the European Patent Application No. 0729933 and in the International Patent Application WO 97/34865 (Preparation 2).
The two other position isomers can be prepared in the following manner:
A compound of formula (IIA): 
is subjected to the action of a dealkylation reagent, in order to obtain the compound of formula (IIB): 
which compound of formula (IIB) is subjected: either to the action of a protective reagent of the diols in basic medium, in order to selectively obtain the product of formula (IIC): 
in which P represents the remainder of a protective reagent of the diols,
which is successively subjected to the action of a protective reagent of the phenol, of a deprotection reagent of the diols, of an alkylation agent then of a deprotection agent of the phenol in order to obtain the compound of formula (IID) corresponding to the trisubstituted product of formula (II) with OH in position 8: 
or successively to the action of a protective agent of the phenol, of an alkylation agent then of a deprotection agent in order to obtain the compound of formula (IIE) corresponding to the trisubstituted product of formula (II) with OH in position 9
By dealkylation reagent, is preferably meant agents such as boron tribromide or aluminium chloride.
The protective reagent of the diols which is reacted on the products of formula (IIB) can be a boron derivative such as boric acid, a trialkyl borate, for example trimethyl or triethyl, or also borax.
By protective agent of the phenol, is meant in particular a halide such as mesyl or tosyl chloride or bromide or also a benzylated derivative such as benzyl tosylate or mesylate.
By deprotection reagent of the diols, is meant in particular a strong acid such as hydrochloric acid, sulphuric acid or paratoluene sulphonic acid or also an oxidizing agent, for example hydrogen peroxide, in the case of protection by a boron derivative.
By alkylation agent, is meant any standard agent known to a person skilled in the art for the alkylation of phenols. For example an alkyl halide such as methyl or ethyl chloride, an alkyl sulphate such as methyl or ethyl sulphate, or also diazomethane can be mentioned.
By deprotection agent, is meant a base such as soda, potash or also sodium or potassium carbonate.
The monosubstituted products of formula (II), in which R2, R3, R4 and R5 represent a hydrogen atom, are prepared according to a similar method to that described in the European Patent Application No. 0729933:
(i) a compound of formula (a): 
in which Oxe2x80x94(Alk) is in meta or para position of the alkylcarboxylic group, (Alk) being as defined previously, is subjected to the action of a halogenation agent in order to obtain the corresponding acyl halide,
(ii) which is subjected to the action of a reagent of formula (b): 
in which R(I) and R(II), identical or different represent an alkyl group containing 1 to 6 carbon atoms, or R(I) and R(II) together with the nitrogen atom to which they are linked, represent a heterocycle with 5 or 6 members, saturated or unsaturated, optionally containing another heteroatom chosen from 0 and N,
in order to obtain a compound of formula (c): 
(iii) which is subjected to the action of a halogenation agent in order to obtain a compound of formula (d): 
in which Hal1 represents a halogen atom,
(iv) which is subjected to the action of a Lewis acid, in order to obtain a compound of formula (e): 
v) which is subjected to a dealkylation reagent in order to obtain the product of formula (IIF) corresponding to the expected monosubstituted product of formula (II): 
The disubstituted products of formula (II), in which R2 represents Oxe2x80x94(Alk) or Oxe2x80x94(CH2)0-3xe2x80x94Ar, R3, R4 and R5 are hydrogen atoms and OH and R2 being in position 8, 9 or 10, are prepared according to the method described above starting from the compound of formula (axe2x80x2): 
in which Oxe2x80x94(Alk) and R2 are in meta or para position of the carboxylic alkyl chain, R2 being an Oxe2x80x94(Alk) or xe2x80x94(CH2)0-3xe2x80x94Ar group, successively to reactions (i), (ii), (iii), (iv) and (v) and the products of formula (IIG) are obtained corresponding to the expected disubstituted products of formula (II): 
The halogenation agent which is reacted on the compound of formula (a) or (axe2x80x2) is for example thionyl chloride, oxalyl chloride or any other agent known to a person skilled in the art for preparing an acid halide.
The reagent of formula (b) is prepared starting with cyclopentanone and a secondary amine, for example diethylamine, piperidine, piperazine or, preferably, morpholine. The operation is carried out in the presence of a strong acid catalyst, for example paratoluene sulphonic acid.
The action of the enamine of formula (b) on the acid halide is preferably carried out in the presence of a tertiary amine such as triethylamine or pyridine.
The halogenation agent which is reacted on the compound of formula (c), or its disubstituted equivalent of formula (cxe2x80x2), can be for example thionyl chloride, phosgene, phosphorus oxychloride or, preferably, oxalyl chloride.
The Lewis acid used to cyclize the compound of formula (d), or its disubstituted equivalent of formula (dxe2x80x2) is for example aluminium chloride, titanium tetrachloride, or preferably ferric chloride, or tin tetrachloride. The reaction, as with those above, can be carried out, for example, in a halogenated solvent such as methylene chloride, chloroform or dichloroethane.
The dealkylation reagent of the compound of formula (e), or its disubstituted equivalent of formula (exe2x80x2) in order to obtain the corresponding phenols is preferably aluminium chloride or boron tribromide.
The products of formula (II) in which R4 is different from the hydrogen atom, are prepared by standard methods of aromatic electrophile and nucleophile substitution known to a person skilled in the art.
The products of formula (II) in which R5 is different from the hydrogen atom are prepared according to methods known to a person skilled in the art and in particular according to the method described in the European Patent Application No. 0729933, i.e. by halogenation then the action of water or of an appropriate alcohol.
The products of formula (II) in which R5 is a hydrogen atom and in which there is a double bond in position 1-2 are prepared according to methods known to a person skilled in the art and in particular according to the method described in the European Patent Application No. 0729933, i.e. by dehydration or dealkoxylation in an anhydrous acid medium.
The products of formula (II) in which the junction between the ring at 5 and the ring at 7 is saturated are prepared according to the standard methods of hydrogenation in particular in the presence of palladium on the carbon of the corresponding double bond.
The introduction of R4, R5 as well as the hydrogenation reaction is preferably carried out on the compounds of formula (IIA), (IID), (IIE), (IIF) or (IIG).
The products of formula (II) in which R2 and R3, in ortho position relative to each other form a ring of xe2x80x94Oxe2x80x94(CRdRe)nxe2x80x94O type as defined previously, are also prepared according to the methods known to a person skilled in the art.
A subject of the invention is also, as intermediate products, the products of formula (IIIa), (IIIb), (IIIc) and (IIId).